The primary objectives of this proposal are to investigate the mechanisms underlying the preferential uptake and sequestration of a variety of compounds and the effect of such events on pulmonary clearance of other circulating substances. Ongoing investigations suggest that specific mechanisms may exist for the uptake and accumulation of drugs in the lung tissue. Accumulation may occur by simple diffusion followed by non-specific tissue binding as in the case of morphine and chlorpromazine. Sodium-dependent, carrier-mediated active transport followed by tissue binding may be important in the accumulation of other compounds such as chlorphentermine. Irrespective of the specific mechanisms by which drug uptake and storage occurs in the lungs, it is apparent that these events will have some impact on the respiratory and non-respiratory functions of the lung. Drug-induced pulmonary phospholipidosis models being developed in this laboratory will be utilized to examine pulmonary clearance of imipramine, phentermine and cyclizine, etc., in comparison with the clearance of their chlorinated congeners, viz., chlorimipramine, chlorphentermine and chlorcyclizine, etc., from systemic circulation. Further, effect of these drugs on pulmonary clearance of endogenous vasoactive hormones such as 5-HT and norepinephrine will be investigated. Isolated perfused lung, lung slice techniques, as well as intact animal preparations from treated and control rats and rabbits will be employed in these pharmacokinetic studies. Understanding the effects on pulmonary clearance of other circulating substances is essential to successful management of clinically significant toxic drug interactions attributable to preferential sequestration of drugs in the lung which lead to drug-induced pulmonary toxicity resulting in a range of pulmonary pathophysiology.